A research team led by a recent BBRF grantee has developed and tested in a first patient a novel protocol designed to identify optimal personalized brain stimulation targets for severe, treatment-resistant OCD. Once identified, the team used these targets to guide precise implantation of a deep-brain stimulation (DBS) device whose subsequent activation resulted in rapid and acute reduction of the patient’s OCD symptoms (62% lower 6 months after the procedure).

The study was led by Andrew Moses Lee, M.D., Ph.D., a 2020 BBRF Young Investigator grantee, and senior team members Andrew D. Krystal, M.D., recipient of BBRF Young Investigator grants in 1997 and 1993, and Edward F. Chang, M.D., all at the University of California, San Francisco. They joined colleagues in reporting in the journal Translational Psychiatry results of their unique FDA-approved clinical trial involving a single OCD patient.

A woman in her 20s, she suffered from “extreme, treatment-refractory OCD,” with symptoms consisting mostly of harm-based obsessions associated with checking compulsions. “These symptoms were disabling, occupied most of her waking hours, caused her to leave nursing school, and prevented her from driving or leaving home,” the team noted. She had not responded to multiple trials of serotonin reuptake inhibitors (SRIs), or to augmentation strategies, outpatient and intensive residential therapy, or transcranial magnetic stimulation (TMS).

TMS, a non-invasive method in which neural stimulation is delivered on an outpatient basis, has been tested in OCD, but is not effective in many patients (the response rate is much higher in patients with depression). Deep-brain stimulation, in contrast, is invasive: it entails brain surgery, remains experimental, and is only considered as a potential treatment option, whether in depression or OCD, in severe cases involving disabling or life-threatening symptoms that have not responded to multiple courses of other therapies.

DBS has been tested previously in a number of OCD patients. The methods used have resulted in responses in about 60% of patients, and average symptom reductions of around 40%. But, the team notes, there has been a “lack of consistency in the response to any individual target” in these DBS trials. This could be due to variations in the underlying circuit abnormalities causing symptoms across these patients, anatomical variation across individuals, or poor engagement of the intended circuit target in specific cases.

“To address these challenges, we developed a protocol that aimed to identify personalized neuromodulation [i.e., brain stimulation] targets,” the researchers explained. They adapted methods commonly used in epilepsy to guide surgical treatment. Several years ago, Dr. Krystal and 2018 BBRF Young Investigator Katherine W. Scangos, M.D., Ph.D., used a similar approach to identify treatment targets prior to implantation of a DBS device for a patient with life-threatening severe refractory depression.

The protocol unfolds in three stages. First, the patient undergoes an invasive procedure to implant a series of electrodes, in this case across a circuit known to be implicated in OCD called the cortico-striato-thalamo-cortical circuit (CSTC). Then, a process called stimulation mapping ensues. Over a period of days, the team delivers varying amounts of stimulation to the implanted electrodes, individually and in various combinations. The aim here is to find the specific sites whose stimulation acutely reduces OCD symptoms. (The patient, if not experiencing symptoms, is given prompts designed to generate symptoms while these tests are under way.) Stimulation of some sites is observed to cause adverse effects; these are avoided in preparing a protocol for therapeutic DBS stimulation. The third phase involves multiple 20-minute stimulation sessions of the top candidate stimulation sites, with actual stimulation and a placebo version delivered randomly (neither the patient nor the doctors delivering the stimulation know when the “real” stimulation is being delivered.) Results of these tests enabled the team to plan where exactly in the brain to implant the DBS device. This surgery was performed 8 weeks after the mapping electrodes were removed. Two weeks after DBS implantation, the device was programmed to deliver optimal clinical improvement, based on the patient’s real-time responses.

All of this work enabled the team to discover that at least in this patient, “high frequency activity” of neural activation within the CTSC circuit correlates with OCD symptom severity. Tests in future subjects will begin to enable the team to say whether this correlation is present in all or many OCD patients, or not. In this case, the preliminary mapping and probing enabled the team to identify two highly specific targets for DBS stimulation to reduce symptoms. These targets are both within the brain’s right ventral capsule (VC), an area involved in connecting the prefrontal cortex and the ventral striatum, which is implicated in emotion processing and behavior.

Combined stimulation of these targets acutely and rapidly reduced the patient’s severe OCD symptoms. Prolonged stimulation of the VC targets via DBS suppressed high frequency activity in the orbitofrontal and cingulate cortices, which were found to be structurally and functionally connected. This result leads the team to describe these sites as “cortical nodes encoding the severity of OCD symptoms.”

“This case provides the first proof-of-concept that invasive brain mapping can be used to guide a novel personalized, multi-site neuromodulation approach to treat refractory OCD,” the team wrote. The results “open up the possibility of personalized neuromodulatory therapies.”

Will the results in this patient generalize to others with severe OCD symptoms? The two stimulation sites identified by preliminary brain mapping are similar but not identical to those targeted in past experiments with DBS. About 40% of OCD patients in those experiments did not respond to DBS. This suggests the importance of performing the preliminary mapping phase of the protocol in other patients, to determine if in some refractory patients alternate stimulation sites might generate a response like the one seen in the just-reported trial. On the other hand, if the stimulation sites used in this study do tend to generalize, it may indicate a circuit dysfunction in severe OCD that is commonplace, and which might be “consistently targeted to achieve therapeutic responses.” This in turn would argue against the need to personalize the targeting, an invasive and difficult procedure for the patient that it would be advantageous to avoid, if possible.

The team also included Joline M. Fan, M.D., 2022 BBRF Young Investigator.